The long-term objective of this research is the detailed characterization of brain and spinal cord cholinergic systems (i.e., those that synthesize and use acetylcholine to communicate with other tissue entities) in terms of anatomic organization, relationship to other chemically identifiable cells, basic biologic mechanisms, and functions as manifested in both normal and pathologic states. The present application focuses on an important but incompletely specified property of central cholinergic neurons, particularly in non-septohippocampal networks, and that is their structural plasticity or capability of modifying their morphologic organization either normally or as a consequence of various experimental manipulations. Surgical intervention in in vivo preparations will be used to trigger plastic neuronal processes in components of hitherto poorly characterized brain cholinergic systems, namely (a) the medial cholinergic pathway innervating medial cortical targets and (b) the cholinergic pontomesencephalotegmental (PMT)- anterior thalamic projection. Specifically, answers are sought to two broad-based questions. First, what are the morphologic and cytochemical characteristics of cholinergic neuronal reorganization following injury to representative projections of the basal forebrain and PMT cholinergic systems? And second, can cholinergic neuronal plasticity in the medial cortical and PMT-anterior thalamic pathways be modified by neurtrophic factors? Methodologies to be used (1) sterotaxic surgical procedures for axotomies, intracerebral infusion of ibotenic acid, and intraventricular administration of nerve growth factor (NGF), NGF antibodies, somatatostatin, and GM1 monosialognaglioside, among other compounds, (2) immunohistochemical demonstration of choline acetyltransferase, NGF receptor, glial fibrillary acidic protein, and cytoskeletal proteins, (3) histochemical and histologic processing for acetylcholinesterase, Nissl substance, and oligodendroglia, (4) anterograde and retrograde tract-tracing procedures, and (5) biochemical techniques for measurement of ChAT and acetylcholine release, the latter by means of microdialysis coupled with high-performance liquid chromatography and electrochemical detection. This research should have relevance for understanding not only basic biologic mechanisms in central cholinergic neurons but also human disorders involving brain cholinergic systems, particularly Alzheimer's disease and senile dementia of the Alzheimer type.
